The present invention is drawn toward compositions and methods for separating an amine or amino acid enantiomer from its counter-enantiomer in order to obtain a high degree of chiral purity.
Effective methods for the separation and recovery of particular enantiomers of biochemicals such as amines and amino acids as well as other types of biochemicals is of great importance in modern technology. This importance is exemplified by the growing need and desire to produce and use optically pure pharmaceuticals and other biochemicals for human and other use. For example, often only one enantiomer of a chemical compound is biologically active or produces a desired effect. Thus, in order for a recipient of a pharmaceutical to receive enough of the biologically active enantiomer, twice the amount of pharmaceutical is generally given (assuming that the enantiomers are represented at about a 50:50 ratio). In other cases, the undesired enantiomer may be toxic or produce side effects. For example, the undesired enantiomer of thalidomide[4] has been known to cause severe malformation in children born to pregnant women who took the drug by prescription for the benefits of the desired enantiomer. Therefore, much research has been conducted in order to produce optically or enantiomerically pure pharmaceuticals such that the biologically active or desired enantiomer may be used in essentially pure forms in order to eliminate the drawbacks discussed above.
There are essentially three theoretical methods that may be used to obtain optically pure compounds for pharmaceutical or other use. First, the desired enantiomer may be synthesized in the desired enantiomeric or optically pure form. Unfortunately this method is often impractical because, in many cases, these types of synthesis methods have not been discovered, or alternatively for those which have been discovered, the production cost of making the pure enantiomer has been prohibitive.
The second method involves separating the desired enantiomer from a mixture containing both enantiomers. However, because the enantiomers differ only in chirality, such processes have proven very difficult to carry out. In some instances, these separations have been accomplished by means of crystallization. For example, tartaric acid as a crystallization platform has been used for such a separation. Though this is a somewhat cost effective method, it is useful in only a minority of cases. In most instances, such separations must be performed using a chromatographic stationary phase and a chromatographic method of separation. However, these type of chromatographic separations have low throughputs and high operating costs.
The third method for chiral separation involves a combination of the two methods described above. In this combination method, an initial chiral intermediate is separated at a relatively high purity followed by additional synthesis steps that further purify the chiral intermediate to a final product without introducing additional chiral impurity. However, with this method, a cost effective chiral separation approach is still needed.
In general, what is often needed to overcome the high cost of performing a chiral separations is to provide a method that allows for high selectivity of the desired enantiomer. As such, in accordance with the present invention, nonchromatographic or equilibrium bind/release separation modes using solid resin phases have been formed to accomplish this result. Before now, solid resin phases of sufficient selectivity and/or stability have not been available to accomplish such an enantiomeric separation function to a degree of purity that is both practical to use and cost effective. This is significant because it is the separation itself that accounts for a large portion of the total cost of making a pure enantiomer product. Thus, by reducing the separation costs, the final selling price of the pure enantiomer may be reduced.
As stated, some research has been done in producing chiral ligands capable of some selectivity between chiral enantiomers of the same compound. Additionally, electrophoresis has been used as well for such chiral separations. However, both of these methods, i.e., chromatography and electrophoresis, provide only low throughputs, and therefore, are not as desired as that described by the present invention. Some articles have described electrophoresis as a separation method and several other articles have discussed the use of such ligands in chromatographic resin phases. Such patents and articles include: U.S. Pat. Nos. 4,001,279 and 4,043,979 issuing to Cram, D. J.; Dotsevi, G., et al., Chromatographic Optical Resolution through Chiral Complexation of Amino ester Salts by a Host Covalently Bound to Silica Gel, J. Amer. Chem. Soc., 97:5, pp 1259-61 (1974); Bradshaw, J. S., et al., Enantiomeric Recognition of Organic Ammonium Salts by Chiral Dialkyl-, Dialkenyl-, and Tetramethyl-Substituted Pyridino-18-crown-6 and Tetramethyl-Substituted Bis-pyridino-18-crown-6 Ligands: comparison of Temperature-Dependent H NMR and Empirical Force field techniques, J. Org. Chem., Volume 55, pp. 3129-37 (1990); Zhang, et al., Enantiomeric Recoqnition of Amine Compounds by Chiral Macrocyclic Receptors, Chem. Rev., Volume 97, pp. 3313-61 (1997); Pirkle, W. H. et al., Chiral Stationary Phases for the Direct LC Separation of Enantiomers, Adv. Chromatography, Volume 27, pp. 73-127 (1987); Armstrong, D. W., et al., Macrocyclic Antibiotics as a New Class of Chiral Selectors for Liquid Chromatoqraphy, Anal. Chem., Volume 66, pp. 1473-1484 (1994); Armstrong, D. W., et al., Optical Isomer Separation by Liquid Chromatoqraphy, Anal. Chem., Volume 59, pp. 84A-91A (1987); Huszthy, P., et al., Entiomeric Separation of Chiral [xcex1-(1-Naphth)Ethyl]Ammonium Perchlorate by Silica Gel-Bound Chiral Pyridino-18-Crown-6 Liqands, Acta Chim Hung, Volume 131, pp. 445-54 (1994); Pirkle, W. H., et al., Chem. Rev., Volume 89, pp. 347-362 (1989), all of which are incorporated herein by reference.
Specifically, Cram has worked with the naphthyl crown compounds including some attachments to solid supports. However, Cram has only been able to show chromatographic separations with ligand bound solid supports, or alternatively, with coated solid supports. Work to accomplish the high selectivity nonchromatographic separation of amines and amino acids via highly stable covalently attached naphthyl crown ether compounds in three separation stages or less has not been previously demonstrated.
The other references cited above disclose procedures for synthesizing either chromatographic resin materials for chiral separations or for synthesizing unbound ligands with chiral selectivity in single phases. Further, none of the references cited above describe any separations other than chromatographic separations. Therefore, it would be desirable to provide compositions and methods of separating enantiomers using nonchromatographic separation techniques that allow for much faster separations at much higher quantities while maintaining lower cost basis for the separation.
The present invention is drawn to compositions and methods, the compositions comprising naphthyl crown ether ligand molecules containing at least two naphthyl groups that are covalently bonded to suitable solid supports and coated by hydrophobic organic solvents. These compositions exhibit selectivity of desired amine or amino acid enantiomers over their counter-enantiomers and derivatives. The composition preferably has an xcex1-value greater than or equal to 4 such that one enantiomer is selected over its counter-enantiomer by a factor of 4 or greater. This allows for the separation of such enantiomers with nonchromatographic resin bed separations of three separation stages or less.
Additionally, a nonchromatographic method of separating an enantomeric molecule from its counter-enantiomer is disclosed comprising (a) flowing a feed solution containing a desired enantiomer and its counter-enantiomer through a separation device having a ligand bound to a solid support wherein the ligand has an affinity for the desired enantiomer and a selectivity of at least 4; (b) selectively forming a complex between the desired enantiomer and the ligand thereby forming a first raffinate having increased purity of the counter-enantiomer; (c) breaking the complex between the desired enantiomer and the ligand with a smaller volume of an aqueous receiving solution in which the desired enantiomer is soluble, or which has greater affinity for such desired enantiomer than does the ligand portion of the composition, or which has a greater affinity for the ligand than does the desired enantiomer, thereby quantitatively stripping such desired enantiomer from the ligand and forming a desired enantiomer enhanced receiving liquid; (d) flowing the desired enantiomer enhanced receiving liquid through a separation device having ligands bound to solid supports wherein the ligand has reverse optical activity as compared to the ligand in step (a) such that the ligand has an affinity for the counter-enantiomer; and (e) selectively forming a complex between the counter-enantiomer and the ligand thereby forming a second raffinate having increased purity of the desired enantiomer. This method can be carried out with the compositions disclosed herein, or with any other composition having an affinity for a desired enantiomer over a counter-enantiomer and a selectivity of at least 4.
Before the present invention is disclosed and described, it is to be understood that this invention is not limited to the particular process steps and materials disclosed herein because such process steps and materials may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only. The terms are not intended to be limiting because the scope of the present invention is intended to be limited only by the appended claims and equivalents thereof.
It must be noted that, as used in this specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9can,xe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the content clearly dictates otherwise.
xe2x80x9cRacematexe2x80x9d or xe2x80x9cracemicxe2x80x9d when referring to feed solutions is intended to include any solution containing both enantiomeric varieties of a molecule, i.e., the desired enantiomer and counter-enantiomer, in approximate equal amounts. The solution may also contain other matter including other contaminants or impurities that are desired to be separated out.
xe2x80x9cRaffinatexe2x80x9d is intended to include the solution that passes through the separation device excluding the molecules or enantiomers that bind to the ligands attached to the solid supports. In some instances, the raffinate will contain the desired enantiomer in high concentration and in some instances the raffinate will contain the desired enantiomer in low concentration, depending on whether the ligand is optically designed to bind to the desired enantiomer or the counter-enantiomer.
xe2x80x9cCounter-enantiomer,xe2x80x9d xe2x80x9cundesired enantiomer,xe2x80x9d or xe2x80x9cnondesired enantiomer,xe2x80x9d generally shall include the chiral molecule that is to be separated out from the desired chiral enantiomeric molecule. The term xe2x80x9cnondesiredxe2x80x9d or xe2x80x9cundesiredxe2x80x9d does not mean that these enantiomers are not desirable for any purpose, only that these molecules are undesired to the extent that the other enantiomeric molecule is one the being focused upon for concentration and/or purification.
xe2x80x9cDesired enantiomerxe2x80x9d or xe2x80x9cdesired moleculexe2x80x9d generally shall include the chiral molecule that the compositions and methods of the present invention are designed to purify, though the counter-enantiomer may desirable in other circumstances or separations.
With these definitions in mind, the invention described herein provides for a sufficiently stable and selective solid resin phase composition and related methods for the separation of desired chiral amines and amino acids from their undesirable enantiomers. Unlike much of the prior art in this area, the separations of the present invention may be carried out utilizing highly desirable and cost effective nonchromatographic separation methods.
The composition is essentially an optically active naphthyl crown ether ligand bonded to a solid support via a covalent bond and then coated with a hydrophobic solvent, thereby forming a highly selective (selectivity factors greater than or equal to 4) nonchromatographic separation resin compound. The compound enables one to separate desired chiral amines, chiral amino acids, and their derivatives from their undesired or counter-enantiomers. The resin compounds of the present invention are highly stable, and thus, may be reused on multiple occasions. Additionally, not only can this composition be used for removing, separating, and/or concentrating certain desired chiral amines or amino acids from their undesired or counter-enantiomers, other impurities as well which may be present may also be separated out.
Specifically, the composition is comprised of at least one ligand covalently bonded to a particulate solid support through a hydrophilic spacer as shown in Formula 1 below:
SSxe2x80x94Axe2x80x94Xxe2x80x94Lxe2x80x83xe2x80x83Formula 1 
where SS is a porous or non-porous particulate inorganic or organic polymer solid support, A is a covalent linkage mechanism, X is a hydrophilic spacer grouping, L is a naphthyl crown ether ligand molecule containing at least two naphthyl groups, and wherein the ligand bound solid support (SSxe2x80x94Axe2x80x94Xxe2x80x94L) is coated with a hydrophobic organic solvent with the proviso that when SS is a particulate organic polymer, Axe2x80x94X may be combined as a single covalent linkage. Exemplary hydrophobic solvents that may be used include methylene chloride, chloroform, and/or dichloroethane, though other hydrophobic solvents may be used. Additionally, in the preferred embodiment, L is defined by a structure depicted below in Formula 2: 
where x is independently from about 2 to 4; y is from about 3 to 8; R is H or preferably a substituted or unsubstituted bulky group independently be selected from the group consisting aliphatic, alicyclic, aromatic, and combinations thereof; and Rxe2x80x2 is independently selected from the group consisting of hydrogen, lower alkyl having from 1 to 16, glycol, aromatic (including naphthyl and anthracene) with the proviso that at least one Rxe2x80x2 is functionalized for attachment or attached to SS through the Axe2x80x94X linkage as shown in Formula 1. With respect to R, if the bulky group is aliphatic, from 1 to 16 carbons can be present in saturated and/or unsaturated form and can be a straight or branched chain. With respect to alicyclic, aromatic, and combinations of alicyclic and aromatic, it is preferred that from 1 to 6 ring structures be present. Alicyclic and aromatic rings may also be heterocyclic in that they contain one or more heteroatoms selected from the group consisting of oxygen, sulphur, and nitrogen in the ring structure. Aliphatic groups may also contain oxygen, sulphur and nitrogen atoms within the chain structure to the extent they are functional.
The SSxe2x80x94Axe2x80x94Xxe2x80x94 portion of Formula 1 is well known for use with ion binding ligands. Preferably solid support xe2x80x9cSSxe2x80x9d is an inorganic and/or organic particulate support material selected from the group consisting of silica, silica gel, silicates, zirconia, titania, alumina, nickel oxide, glass beads, phenolic resins, polystyrenes and polyacrylates. However, other organic resins or any other hydrophilic organic and/or inorganic support materials meeting the above criteria can also be used. The use of organic ion binding ligands attached to an SSxe2x80x94Axe2x80x94Xxe2x80x94 solid support by means of a covalent linkage spacer grouping is illustrated in U.S. Pat. Nos. 4,943,375; 4,952,321; 4,959,153; 4,960,882; 5,039,419; 5,071,819; 5,078,978; 5,084,430; 5,173,470; 5,179,213; 5,182,251; 5,190,661; 5,244,856; 5,273,660; and 5,393,892. These patents, which disclose various spacers that can be used in forming an organic ligand attached to a solid support, are incorporated herein by reference.
If an inorganic solid support is used, a hydrophillic spacer is grouped to a silicon, carbon, nitrogen, oxygen, or sulfur atom and is further covalently bonded to a particulate porous and/or nonporous solid support. When the solid support SS is an inorganic material such as silica, silica gel, silicates, zirconia, titania, alumina, nickel oxide, and/or glass beads, the covalent linkage A is a silane such that Axe2x80x94X may be represented by Formula 3 below: 
wherein each Z can independently represent members selected from the group consisting of Cl, Br, I, lower alkyl, lower alkoxy, substituted lower alkyl or substituted lower alkoxy and Oxe2x80x94SS. As used herein, lower alkyl or lower alkoxy means a group having 1 to 16 carbon atoms. Additionally, X is preferably a spacer grouping having the formula:
(CH2)a(OCH2CHR1CH2)bxe2x80x83xe2x80x83Formula 4 
wherein R1 is a member selected from the group consisting of H, SH, OH, lower alkyl, and aryl; a is an integer from 3 to about 10; and b is an integer of 0 or 1.
If an organic polymer or resin solid support is used, i.e., SS is a particulate polymeric organic solid support matrix such as polyacrylate, polystyrene, and/or polyphenol, the ligand will then generally contain a functional grouping reactive with an activated polar group on the polymer. When the A and X are combined, they may be represented by Formula 5 below:
xe2x80x94(CH2)xxe2x80x94(Y)yxe2x80x94(CH2)zxe2x80x94xe2x80x83xe2x80x83Formula 5 
where y is 0 or 1; x and z are independently whole numbers from 0 to 10; and Y is member selected from the group consisting of 0, S, Cxe2x95x90N, CO, CONH, CSNH, COO, CSO, NH, NR, SO, SO2, SO2NH, C6H4, and CH2C6H4 where R is lower alkyl with the proviso that at least one of x, y and z must be at least 1.
It is to be emphasized that the present invention does not reside in the discovery of the SSxe2x80x94Axe2x80x94Xxe2x80x94 portion of Formula 1. Rather, it is the discovery that the optically active naphthyl crown ether ligands covalently bonded to solid supports and coated with a hydrophobic solvent exhibits the ability to nonchromatographically separate enantiomers of chiral amines and/or chiral amino acids.
The preferred method involves utilizing up to three separation stages in a nonchromatographic mode of operation, thus, greatly increasing the product throughput and economic efficiency of any given system despite its size. More particularly, the method for separating such desired amine or amino acid enantiomers from an admixture containing the counter-enantiomer of the chiral amine and/or chiral amino acid (and other non-desired chemicals or particulates) in a common solution is carried out by selectively forming a complex between the desired amine or amino acid enantiomer with the compositions of the present invention described above. These compositions have at least a selectivity factor of 4 in each of up to three separation stages, though one or two separation stages is also functional and within the scope of this invention.
The separation is effectuated by fixing the naphthyl crown ether containing solid support coated with a hydrophobic solvent in a separation device such as a column and flowing the source solution containing a mixture of the two enantiomers of the chiral amine and/or chiral amino acid through the support mass. Specifically, the steps of a preferred method include (1) flowing the admixture containing the desired and counter-enantiomer in a solvent such as water or alcohol through the column packed with the optically active naphthyl containing crown ether ligand solid supported materials coated with a hydrophobic solvent, (2) allowing the ligand to selectively complex with the desired enantiomer, and (3) breaking the complex of the desired enantiomer from the compounds to which the desired enantiomer has become attached by flowing a complex breaking receiving liquid in much smaller volume than the volume of solution originally passed through the column to remove and concentrate the desired enantiomer in solution in the receiving liquid. At this point, the first separation has been effectuated.
Next, the receiving liquid containing a more concentrated amount of the desired enantiomer is then adjusted with solvent addition and/or salt addition to a state where the desired amine or amino acid enantiomers are again capable of binding to the solid supported ligands. The adjusted solution is then run through a separation device containing a naphthyl crown ether ligand of opposite optical or chiral activity bonded to the solid support and coated with a hydrophobic solvent to selectively remove in a nonchromatographic mode a large portion of the remaining counter-enantiomer. Thus, the process of complexation in the second stage is similar to that for the initial separation stage other than the bound ligand used is of the opposite chirality. The second stage may be repeated by again utilizing a ligand of the opposite chirality than that of the first stage such that an even greater purity may be obtained if desired. Whether or not a second or third stage is needed will largely depend on the xcex1-value and desired purity. A reason that it is desirable to conduct the first stage of separation by binding the desired enantiomer to the composition in the separation device is that the counter-enantiomer can be removed along with other undesired chemicals or particulates. If one were to engineer the separation such that the desired enantiomer was obtained in the raffinate after the first stage, then other impurities would remain present with the desired enantiomer. However, though conducting a separation that begins with collecting the desired enantiomer in the raffinate is less desirable from an engineering perspective, it is still within the scope of the present invention.
An xcex1-value of 4.0 indicates a four-fold preference for one enantiomer over its counterpart. Thus, if one is dealing with an xcex1-value of 4.0, then three separations are needed to achieve a 98.5% purity of one enantiomer over the other, assuming a racemic starting solution. Larger xcex1-values lead to either greater purity and/or fewer separation stages. Technologies that can achieve substantial separation in three or less stages can offer significant process benefits both economically and from an engineering perspective. Table 1 below shows a sample of enantiomeric purity obtained as a function of various xcex1-values at various numbers of separation stages for the nonchromatographic system of the present invention, assuming a racemic composition is provided for use in stage one.
From this table, it is table, it is apparent that the higher the xcex1-value, the fewer the number of separation stages required to reach 99% enantiomeric purity. For an xcex1-value of 5 (not shown), the use of only three stages allows one to obtain  greater than 99% purity.
If desired, the process also allows for recovery of any of the desired amines or amino acids that were not collected during the first stage of separation, i.e., bleed through of the desired enantiomer of the chiral amine and/or chiral amino acid. The solution that remains after most of the desired amine or amino acid has been collected during stage one is called the raffinate. The raffinate containing a minority of the desired amino acid from the initial separation stage may be treated by passing the raffinate through an additional column or columns containing the optically active enantiomer containing crown ether solid supported and coated materials to selectively complex and thus remove a portion of the desired enantiomer from the raffinate. Though it is not required, the use of a smaller enantiomer containing crown ether ligand may be desired to collect the desired amine or amino acids that were not collected during the initial separation stage. Once this is completed, the remainder of the process is similar to the initial separation stage.
Though the compositions and methods describe a preferred system of separation, i.e., three separation stages utilizing ligands of alternating chiralities between the first and second/third stages, other systems may be developed utilizing these principals. For example, one may design the composition such that the undesired or counter-enantiomer in the first column separation is bound to the ligands. Thus, the raffinate would contain the majority of the desired molecular enantiomer, though the use of such a method can leave impurities in the raffinate with the desired enantiomer. To alleviate this, a subsequent stage where the desired enantiomer is bound to the resin can be carried out. These and other combinations of separations are within the scope of the invention. Additionally, the size of the crown ether may be adjusted within the parameters described in order to functionalize or modulate the separation device for maximum efficiency. For example, larger macrocycles can be used for the separation of larger molecules.
Additionally, a nonchromatographic method of separating a desired enantiomer from its counter-enantiomer is disclosed herein that does not necessarily require the ligand bound solid supports of the present invention. With this method, any ligand bound solid support that is optically active or selective of one enantiomer over another may be used. This method comprises (a) flowing a racemate feed solution containing a desired enantiomer and its counter-enantiomer through a separation device having a ligand bound to a solid support wherein the ligand has an affinity for the desired enantiomer over its counter-enantiomer at a selectivity of at least 4; (b) selectively forming a complex between the desired enantiomer and the ligand thereby forming a first raffinate having increased purity of the counter-enantiomer; (c) breaking the complex between the desired enantiomer and the ligand with a smaller volume of an aqueous receiving solution in which the desired enantiomers are soluble, or which has greater affinity for such desired enantiomers than does the ligand portion of the composition, or which has a greater affinity for the ligand than does the desired enantiomers, thereby quantitatively stripping such desired enantiomers from the ligand and forming a desired enantiomer enhanced receiving liquid; (d) flowing the desired enantiomer enhanced receiving liquid through a separation device having ligands bound to solid supports wherein the ligand has reverse optical activity as compared to the ligand in step (a) such that the ligand has an affinity for the counter-enantiomer; and (e) selectively forming a complex between the counter-enantiomer and the ligand thereby forming a second raffinate having increased purity of the desired enantiomer.
Though this method does not require the specific compositions of the present invention, the use of the compositions described herein are highly functional. For example, the ligand bound solid support coated with organic solvent of the present invention have an affinity for desired amine or amino acid enantiomers over their undesired or counter-enantiomer, and thus, are functional within the context of this method.
As stated previously, the composition of the present invention is a naphthyl crown ether ligand having at least two naphthyl groups bound to the solid support. The ligand bound solid support should also be coated with a hydrophobic organic solvent as described herein. Additionally, steps (d) and (e) may be repeated, i.e., a third stage or phase of separation, to increase the purity of the desired enantiomer.
Even the raffinate may be purified by the additional steps of (i) collecting the first raffinate of step (b); (ii) flowing the first raffinate containing a small amount of the desired enantiomer and a large amount of its counter-enantiomer through a separation device having a ligand bound to a solid support wherein the ligand has an affinity for the desired enantiomer and a selectivity of at least 4; (iii) selectively forming a complex between the desired enantiomer and the ligand; (iv) breaking the complex between the desired enantiomer and the ligand forming a racemate feed solution; and (v) repeating steps (a) to (e). Though this method of purifying the raffinate [steps (i)-(v)] is shown in conjunction with the nonchromatographic method of separating a desired enantiomer from its counter-enantiomer [steps (a)-(e)], it is to be noted that steps (i)-(v) may be carried out independently of steps (a)-(e). However, if carried out in conjunction with the nonchromatographic method described in steps (a)-(e), only steps (a)-(b) need to be carried out in order to practice the method shown in steps (i)-(v).
When investigating the suitability of a particular resin-bound separation process, the following factors are often important: (1) resin consumption; (2) solvent usage; (3) productivity, e.g., chemical, optical, and volume yield; (4) total number of separation steps; and (5) capital costs. The nonchromatographic separation method of the present invention compares favorably to current industry practice. For example, the system of the present invention provides reduced number of process steps; high chemical, optical, and volume yields; high feed throughput; more open-ended solvent choice; minimized solvent usage; and low resin consumption.
Reduced number of process steps are achieved in part due to the fact that the ligands of the present invention display both high chemo- and enantio-selectivity, allowing for simultaneous chiral resolution and chemical separation. High chemical, optical, and volume yields are achieved due to the large capacity of the ligands of the present invention for a single enantiomer on each load cycle. The high selectivity also results in high yield throughputs and close to 100% time usage of the system for feed introduction. Additionally, because the ligands of the present invention are bound to solid supports as described, the covalent linkage provides for long life and multiple recycling capabilities. This feature also allows the user to choose the best solvent for the specific results desired, thus, the solvent choice is deemed open ended. Because high feed concentrations can be used and because feeds can be flowed through nearly continuously, the amount of solvent used may be drastically reduced. Also, because of the highly efficient use of the capacity of the ligands bound solid supports as well as their high stability, there is low resin consumption. Conversely, with chromatographic techniques, low yields and high solvent consumption are often realized.
The chiral separations described in the present invention have many possible applications. For example, in the pharmaceutical industry, these separations may be used for analysis, drug development, and commercial production. During the drug discovery process, extensive screening of available compounds is performed along with animal testing. Thus, small quantities of optically pure drug are often needed quickly to screen candidates. Matrix versatility and rapid throughput are often also essential. Additionally, during pre-clinical and clinical development stages, the requirements for optically pure drug quantities can increase dramatically, e.g., from several grams to 100 kilograms. Optically pure drug can also be needed for animal studies, e.g., pharmacokinetics, metabolism, tissue distribution, and safety, and human clinical studies in Phases I, II, and III. Again, time is often critical in these studies, thus, a rapid separation system as described herein would be advantageous. Further, during product launch and production, large amounts of racemate, i.e.,  greater than 25 tons/year, with total process costs well under the targeted kg drug product price are important to these industries.
Amino acid separation represents another specific application of the present invention. Amino acids are important synthesis precursors (in particular for pharmaceuticals) such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Specialized types of amino acids for synthesis applications represent a growing field in the biotechnology industry. Applications include peptide hormones and growth factors, immunologic antigens, enzyme substrates, receptors and ligands, chemical drugs, bioactive peptides for research, combinatorial chemistry, drug discovery, pesticides, and artificial sweeteners, to name a few. Thus, amino acids represent an important class of compounds that can benefit from more efficient separation technologies.